Depot formulation

ABSTRACT

A pharmaceutical long acting depot composition is provided as an aid to smoking cessation treatment. The formulation comprises a therapeutically effective amount of varenicline or its pharmaceutically acceptable derivative and pharmaceutically acceptable excipients. The process of preparation of the formulation is also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/412,612 filed May 15, 2019, which claims the benefit of IndianProvisional Patent Application Serial Number 201821018318 filed on May16, 2018, the contents of both of which are hereby incorporated byreference in their entirety.

FIELD OF INVENTION

The present invention relates to depot formulation comprisingvarenicline, or pharmaceutically acceptable salts thereof, andpharmaceutically acceptable excipients. The present invention alsorelates to processes for making such a formulation and use of the saidformulation as an aid to smoking cessation treatment.

BACKGROUND OF INVENTION

Smoking is the leading preventable cause of death worldwide.Smoking-related diseases kill an estimated 438,000 Americans each year,including those affected indirectly, such as premature babies of smokingmothers and victims of ‘secondhand’ smoke. Millions of people in theworld have at least one serious illness caused by smoking. Smokingcauses chronic lung disease, cardiovascular disease and stroke. Smokingmay be a cause of several cancers (in addition to lung cancer) and hasbeen linked to slowed healing of wounds, infertility and stomach ulcers.

Many factors make quitting smoking difficult. Most smokers trying toquit fail several times before they are able to break the habit. Smokerswho are trying to quit are faced with social influences that maypersuade them to conform and continue smoking. Cravings are easier todetain when one's environment does not provoke the habit. If a personwho stopped smoking has close relationships with active smokers, he orshe is often put into situations that make the urge to conform moretempting. For example, if an acquaintance offers a cigarette as a politegesture, the person who has stopped smoking will be more likely to breakhis commitment of quitting smoking. Smokers with major depressivedisorder may be less successful at quitting smoking than non-depressedsmokers. Thus, smoking is a notoriously difficult habit to break.Relapse (resuming smoking after quitting) can also happen which has beenrelated to psychological issues such as low self-efficacy, ornon-optimal coping responses however, psychological approaches toprevent relapse have not been proven to be successful.

There are various methods of breaking the smoking habit. Smokingcessation therapies are more likely to succeed for patients who aremotivated to stop smoking and who are provided additional advice andsupport. The patients are also provided with appropriate educationalmaterials and counseling to support the quit attempt. Some methodsinvolve medication alone. Most smokers who try to quit, do so withoutany assistance, however, only 3% to 6% of such attempts are successful.The simplest medication regimen involves administering nicotine ingradually diminishing doses. Nicotine patches or lozenges are used toquit smoking habit. The goal of these slow-release preparations is tomaintain the subject in the comfort zone by keeping the blood nicotineconcentration constant throughout the day. Over several weeks oftreatment, the blood concentration of nicotine is gradually lowered.However, the person trying to quit smoking can easily remove the patchesor stop taking lozenges if he or she gets demotivated to quit smokingleading to failure of the treatment.

Varenicline is the first line treatment approved by FDA for use as anaid to smoking cessation. It remarkably binds with high affinity andselectivity at α₄β₂ neuronal nicotinic acetylcholine receptors whichproduces agonist activity, while simultaneously preventing nicotinebinding to these receptors and this leads to efficacy of varenicline insmoking cessation. Varenicline decreases the urge to smoke and reduceswithdrawal symptoms and may help in some relapsed smokers.

Varenicline is available commercially as CHANTIX, an oral immediaterelease tablet containing varenicline tartrate in the strengthequivalent to 0.5 mg and 1 mg free base. The dosage regimen includesadministering 0.5 mg once daily on days 1-3 and 0.5 mg twice daily ondays 4-7. Once the dosing titration has been successfully completed,patients are advised to take 1 mg twice daily for an additional elevenweeks. Patients that successfully stop smoking under the regimen areadvised to take an additional 12 week course of treatment to increaselikelihood of long-term abstinence.

US 2006/0084656 provides an intranasal, buccal, sublingual or pulmonarydosage forms of varenicline.

US 2004/0235850 provides storage stable pharmaceutical dosage form ofvarenicline adducts with certain excipients.

US 2008/0181933 provides a chewing gum composition of vareniclinecomprising a water insoluble base portion and a water-soluble portion.

However, relative to an oral dosage form, delivery of varenicline via atransdermal composition would be a preferred choice by patients who havedifficulty in swallowing tablets, capsules or other solids. Also, thetablet dosage form of varenicline can produce a certain level of nauseain patients. Thus, to reduce these side effects, transdermal compositionof varenicline are also provided wherein a gradual release of thevarenicline via skin layers might reduce the incidence of nausea andenhance the patient compliance and desirability of the drug to a largerpatient population requiring its use.

WO 2007/01296 provides transdermal composition comprising varenicline orits pharmaceutically acceptable salt or prodrug form.

However, it is likely that if the person gets demotivated to quitsmoking during the treatment and experience a strong urge to smoke, heor she will stop applying varenicline transdermal patch by removing itfrom the application site thereby discontinuing the treatment. Hence,adherence to varenicline transdermal patch treatment is oftensub-optimal.

Thus, there is an unmet need to provide an alternate dosage form such asa depot formulation, which would provide higher compliance rate alongwith maintaining therapeutic levels of the drug in the patient's systemfor days or weeks at a time. A depot formulation may provide conveniencefor a patient in need of chronic medication. By delivering drug withoutexposure to the GI tract, the potential issue of drug degradation isalso avoided. Moreover, a depot formulation may provide bettercompliance due to the infrequent dosing regimen and convenience.

Varenicline is therefore a good drug candidate for incorporation intosustained delivery devices, where the patients would be treated for longtime periods with just one application. Hence, a drug deliverytechnology, especially depot preparations which can reduce the totalnumber of such administration and maintain the plasma drug levels forlonger time would be preferred. Such reduction in frequency of drugdosing in practice may be achieved by formulating injectable depotsystem that are capable of releasing drug in a slow but predictablemanner and consequently improve patient compliance. Depot injectionsallow careful control of drug usage (as opposed to orally administereddrugs), where overall treatment efficacy and/or side effects may beidentified. Furthermore, it is easy to identify defaulters and prepareinterventions. These long acting depot formulations of varenicline canhave the potential to not only boost the therapeutic benefit in mostcases, also reduce any unwanted events, such as reduce the risk ofaccidental or deliberated overdose and maintain a stable release ratefor several weeks, several months or longer to avoid the drawbacks oforal administration such as nausea, poor bioavailability, high frequencyof administration, possible toxicity and inadequate individualizabledosing. The long acting depot formulation of varenicline of the presentinvention can address the problems of fluctuating drug concentration andwill provide continuous stimulation of receptors prolonging the durationof action and thus improving patient compliance.

OBJECT OF THE INVENTION

An object of the present invention is to provide a pharmaceuticallong-acting depot composition comprising varenicline or itspharmaceutically acceptable derivatives having improved systemicabsorption.

Another object of the present invention is to provide a long actingdepot formulation comprising varenicline or its pharmaceuticallyacceptable salts and one or more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a long actingdepot formulation comprising varenicline or its pharmaceuticallyacceptable salts wherein the particle size of the drug is about 0.5-100μm.

Another object of the present invention is to provide a process ofpreparing a long acting depot formulation comprising varenicline or itspharmaceutically acceptable salts and one or more pharmaceuticallyacceptable excipients.

Another object of the present invention is to provide an aid to smokingcessation treatment by administering a long acting depot formulationcomprising varenicline or its pharmaceutically acceptable salt and oneor more pharmaceutically acceptable excipients.

Another object of the present invention is to provide a method forreducing nicotine addiction, aiding in the cessation of, or lesseningof, tobacco use in a subject by administering a long acting depotformulation comprising varenicline or its pharmaceutically acceptablesalts and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

According to an aspect of the present invention, there is provided apharmaceutical long-acting depot composition comprising varenicline orits pharmaceutically acceptable derivatives having improved systemicabsorption.

According to an aspect of the present invention, there is provided along acting depot formulation comprising varenicline or itspharmaceutically acceptable salts and one or more pharmaceuticallyacceptable excipients.

According to second aspect of the invention, there is provided a longacting depot formulation comprising varenicline or its pharmaceuticallyacceptable salts wherein the particle size of the drug is about 0.5-100μm.

According to third aspect of the present invention there is provided aprocess for preparing a long acting depot formulation comprisingvarenicline or its pharmaceutically acceptable salts and one or morepharmaceutically acceptable excipients.

According to fourth aspect of the present invention, there is providedan aid to smoking cessation by administering long acting depotformulation comprising varenicline or its pharmaceutically acceptablesalts and one or more pharmaceutically acceptable excipients.

According to fifth aspect of the present invention there is provided amethod for reducing nicotine addiction, aiding in the cessation of, orlessening of, tobacco use in a subject by administering a long actingdepot formulation comprising varenicline or its pharmaceuticallyacceptable salts and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

Smoking cessation with varenicline involves administration of tablets of0.5 mg and in a fixed schedule orally daily. For most drugs, such asvarenicline, depending on the dose, it may be possible to reduce suchadministration frequency from daily to once or twice monthly or evenlonger (6 months). This will enable the person attempting to quitsmoking to get continuous dose of varenicline providing more complianceand avoiding the chances of irregular doses.

Varenicline salt is freely soluble in water and varenicline base ispractically insoluble in water. Thus, it is a critical aspect of presentinvention to provide a pharmaceutical formulation which will provide thetherapeutic amount of varenicline or its pharmaceutically acceptablesalt for a long duration of time by controlling the release rate toachieve the desired pharmacologic effect and improved systemicabsorption. The inventors of present invention after rigorousexperimentation considering the physicochemical properties ofvarenicline or its pharmaceutically acceptable salts and to achieve thedesired pharmacokinetic profile of formulation for longer duration oftime, provided a pharmaceutical long acting depot formulation comprisingvarenicline or its pharmaceutically acceptable salts with one or morepharmaceutically acceptable excipients.

The term “therapeutically effective amount” or “effective amount” issuch that when administered, the pharmaceutical composition results inthe inhibition of the systemic infection. The dosage administered to apatient can be as single or multiple doses depending upon a variety offactors, including the drug's administered pharmacokinetic properties,the route of administration, patient conditions and characteristics(sex, age, body weight, health, size, etc.), and extent of symptoms,concurrent treatments, frequency of treatment and the effect desired.

The term “treatment” or “treating” of a disease, virus or conditionrefers to executing a protocol that may include administering one ormore drugs to a patient, in an effort to alleviate signs or symptoms ofthe disease, virus or condition. Alleviation can occur prior to signs orsymptoms of the disease, virus or condition appearing, as well as aftertheir appearance. Thus, treating or treatment includes reducing,preventing or prevention of the disease, virus or condition. Inaddition, treating or treatment does not require complete alleviation ofsigns or symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient.

The term “reduced initial burst release” as per the present inventionmeans the reduction in release of active ingredient from the dosage format initial time points. The release of active ingredient in first houraccording to the present invention is less than 35%, less than 30%, lessthan 235%, less than 20%, less than 15%, less than 10%, less than 5%, orless than 1%. The formulations of the present invention are preferablyinjectable preparations. Injectable formulations of the presentinvention are typically formulated as aqueous suspensions. Sterileinjectable formulations can be prepared according to techniques known inthe art using suitable carriers, excipients, dispersing or wettingagents, and suspending agents. The injectable formulations may besterile injectable suspensions in a nontoxic, parenterally acceptablediluent or solvent. Among the acceptable vehicles and diluents orsolvents that may be employed are water for injection, isotonic dextrosesolution, Ringer's solution, isotonic sodium chloride solution, andsuitable aqueous solvents and the like useful and safe for parenteraladministration. In addition, sterile fixed oils or fatty esters areconventionally employed as solvents or suspending media.

The term “parenteral” as used herein refers to routes selected fromsubcutaneous (SC), intravenous (IV), intramuscular (IM), intradermal(ID), intraperitoneal (IP) and the like.

The term “long acting” as used herein refers to a pharmaceutical depotformulation which provides prolonged, sustained or extended release ofthe varenicline or its pharmaceutically acceptable salt to the generalsystemic circulation of a subject or to local sites of action in asubject. This term may further refer to a pharmaceutical depotformulation which provides prolonged, sustained, controlled or extendedduration of action (pharmacokinetics) of the active substance in asubject.

The term “pharmaceutical depot formulation” or “long acting depotformulation” includes injection preparations, such as liquid dosageforms (liquids, liquid dispersions, suspensions, solutions, emulsions),gels, implants (rods, rings), biodegradable or non-biodegradablemicroparticles/microspheres in the form of controlled releaseformulations, lyophilized formulations, delayed release formulations,extended release formulations, pulsatile release formulations, and mixedimmediate release and controlled release formulations etc. may also beenvisaged under the ambit of the invention.

The term “biodegradable” as used herein refers to a component whicherodes or degrades at its surfaces over time due, at least in part, tocontact with substances found in the surrounding tissue fluids, or bycellular action.

Varenicline, which is the generic name for7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino [2,3-h] [3]-benzazepine,(2R, 3R)-2,3-dihydroxybutanedioate, has the following structure:

The term “varenicline” is used in broad sense to include not only“varenicline” per se but also its pharmaceutically acceptable salts,pharmaceutically acceptable solvates, pharmaceutically acceptablehydrates, pharmaceutically acceptable enantiomers, pharmaceuticallyacceptable esters, pharmaceutically acceptable derivatives,pharmaceutically acceptable hydrate, pharmaceutically acceptablepolymorphs, pharmaceutically acceptable isomer, pharmaceuticallyacceptable tautomer, pharmaceutically acceptable anhydrate,pharmaceutically acceptable prodrugs, pharmaceutically acceptablecomplexes etc.

The present invention provides long acting depot formulations comprisinga therapeutically effective amount of varenicline base. In someembodiments, the pharmaceutical depot compositions may comprise anyother pharmaceutically acceptable salt of varenicline including, but notlimited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate,phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate,nitrate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, tocopheryl succinate, suberate, sebacate, fumarate, maleate,butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, tartrate, methanesulfonate, propanesulfonate,naphthalene-2-sulfonate, p-toluenesulfonate, mandelate and the likesalts. Preferred salts include tartrate, succinate, fumarate, chlorideand sulfate, preferably the tartrate. In certain embodiments, the depotformulations contain varenicline as the free base.

Preferably, the disclosed depot formulations containing varenicline orits acceptable salt may be administered to the subject in need thereofonce in every three days, once weekly once in every two weeks, once amonth, once in every two months, once in every three months, or once inevery 6 months. In particular, the long acting depot formulation of thepresent invention provide a dosing regimen which ranges from once inthree days to once every 6 months.

In some embodiments, the dose of varenicline ranges from about 0.05 mgto about 5 mg per day, from about 0.1 mg to about 5 mg per day, fromabout 0.25 mg to about 2.5 mg per day, from about 0.5 mg to about 2.5 mgper day, or from about 1 mg to about 2.5 mg per day. In an embodiment,the typical recommended monthly dosage regimen ranges from about 1.0 mgto about 200 mg. The depot formulations disclosed herein can deliver adaily therapeutic dose of varenicline for a period of at least 1 week,at least 2 weeks, at least 4 weeks, at least 8 weeks, or at least 12weeks. In some cases, the depot formulation is designed to deliver atherapeutic dose of varenicline for a period of about 2 weeks, about 4weeks, about 8 weeks, about 11 weeks, or about 12 weeks.

In some persons, some neuro-psychiatric side effects are observed afteradministration of titration dose of varenicline formulations accordingto recommended schedule due to reduced tolerability. To overcome thisproblem, the long acting depot formulation of present invention can beadministered after one week of oral dosage form to establish tolerance,i.e., after achievement of steady state in 4-7 days. Thus, in anembodiment of present invention, the depot formulation of presentinvention is administered in combination with the oral administration ofvarenicline formulation. In a preferred embodiment of present invention,varenicline is administered orally for 1 week followed by administrationof depot formulation of present invention once in every two weeks, oncea month, twice a month, once in every two months, once in every threemonths or once every 6 months, such that varenicline is released fromdepot formulation of present invention at a determined rate. Alsoprovided herein are kits including an orally administered vareniclinedosage form component and a depot dosage form component. The prescribingphysician may provide the oral dosage component to the patient with theappropriate dosing titration schedule. Upon successful completion of theoral titration, the patient can return to the physician to receive thedepot formulation.

In an embodiment, the amount of varenicline or pharmaceuticallyacceptable salt thereof in the formulation of present invention is about1% to about 50% w/v of the total depot composition. In preferredembodiment, the amount of varenicline in the formulation of presentinvention is about 5% to about 40% w/v of the total formulation. In anembodiment, the amount of varenicline in the formulation of presentinvention is about 30-180 mg varenicline of total formulation. In otherembodiments, varenicline is present in an amount form 40-150 mg, 50-140mg, 60-120 mg, 70-100 mg, or 75-90 mg, relative to the total weight ofthe formulation.

In one embodiment, the present invention provides a long acting depotformulation comprising a therapeutically effective amount of vareniclineor any other pharmaceutically acceptable salt in a depot form suitablefor parenteral administration at a medically acceptable location in asubject in need thereof.

Further, the long acting depot formulations of present invention provideequal or superior therapeutic efficacy to the commercially availabledosage form, with reduced incidence and/or severity of side effects atthe local and/or systemic levels.

The present invention provides long-acting depot formulations comprisingvarenicline or its pharmaceutically acceptable salt in the form of anaqueous depot suspension injection. According to one embodiment, thepharmaceutical depot formulation is in the form of microspheres,implants, cubosomes, hexosomes, solutions, suspensions, microemulsions,in-situ gelling system and the like, that are suitable for subcutaneousor intramuscular administration of varenicline base or its salts.According to another embodiment, the long acting depot formulation ofpresent invention comprising varenicline or its salts can be deliveredby biodegradable or non-biodegradable carrier/s.

In some embodiments, the pharmaceutical depot formulations of thepresent invention include, but are not limited to, suspensions ofvarenicline or a pharmaceutically acceptable salt thereof in water, oilor wax phase; poorly soluble polyelectrolyte complexes of varenicline ora pharmaceutically acceptable salt thereof; “in-situ” gel-formingmatrices based on the combination of water-miscible solvent withvarenicline or a pharmaceutically acceptable salt thereof; andbiodegradable polymeric microparticles with incorporated varenicline ora pharmaceutically acceptable salt thereof.

Microspheres, implants and gels are the forms of biodegradable polymericdevices used in prolonging the release of drugs in the body. Besidesbiodegradable systems, there are non-biodegradable implants and infusionpumps that can be worn outside the body in case if the person showsundesirable side effects due to smoking cessation and nicotinewithdrawal. In a preferred embodiment, dosage form with biodegradablepolymers can be used, according to present invention.

In certain embodiments, the dosage forms include, but are not limitedto, biodegradable injectable depot systems comprising biodegradablepolymers such as polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA)75:25, PLGA 50:50, polycaprolactone (PCL), linear polyhydroxy alkanoate(PHA), polybutylene succinate (PBS), polybutylene succinate adipate(PBSA); polybutylene adipate (PBA); polybutylene adipate terephthalate(PBAT), polycarbonates, polyurethanes; non-PLGA based injectable depotsystems comprising polymers such as ethylene-vinyl acetate (EVA),polyurethane, and injectable biodegradable gels or dispersions.

In particular, the pharmaceutical depot compositions of the presentinvention are in the form of injectable microparticles wherein thevarenicline or pharmaceutically acceptable salt thereof is entrapped ina biodegradable or non-biodegradable carrier. The microparticulatecompositions of the present invention may comprise a water-in oil-inwater double emulsion.

In embodiment, the present invention provides parenteral pharmaceuticallong acting depot compositions of varenicline in an aqueous suspension.

In some embodiments, the varenicline or salt thereof is provided in thedepot formulation as particle. In some embodiments, the varenicline orsalt thereof can be characterized by a d₁₀ of about 0.5 micron to about10.0 micron, a d₅₀ of about 1 micron to about 40 microns and a d₉₀ ofabout 20 microns to about 100 microns. In other embodiments, the sizedistribution of the varenicline particles in the formulation has a d₁₀of about 1 micron to about 5 microns, a d₅₀ of about 5 microns to about30 microns and a d₉₀ of about 40 microns to about 80 microns.

The limited solubility of varenicline base or its salt in water coupledwith controlled particle size is utilized for the preparation of longacting depot formulation of present invention.

Depending on the dosage form, the long acting depot formulation ofpresent invention comprises of varenicline or its pharmaceuticallyacceptable salt and one or more pharmaceutically acceptable excipientsselected from fluid containing stabilizer, matrix forming agent,viscosity enhancing agent, one or more of a preservative, a buffer, anisotonizing agent, lipids and the combination thereof. Particularingredients may function as two or more of these agents simultaneously.e.g. behave like a preservative and a buffer, or behave like a bufferand an isotonizing agent.

The fluid containing stabilizer of the present invention also act aswetting agent or suspending agent and ensure complete wetting of themicroparticles by the injection vehicle and thus stabilizing thevarenicline base or its pharmaceutically acceptable salt in thecomposition. Suitable fluid containing stabilizer for use according tothe present invention are polyoxyethylene derivatives of sorbitanesters, e.g. polysorbate 20 and polysorbate 80, lecithin,polyoxyethylene ethers, polyoxypropylene ethers, sodium deoxycholate.Preferred wetting agents include polysorbate 20 (Tween 20), polysorbate40 (Tween 40), and polysorbate 80 (Tween 80). Other fluid containingstabilizer suitable for use include various polymers, low molecularweight oligomers, natural products, and surfactants, including nonionicand ionic surfactants, such as cetyl pyridinium chloride, gelatin,casein, lecithin (phosphatides), dextran, glycerol, gum acacia,cholesterol, tragacanth, stearic acid, benzalkonium chloride, calciumstearate, glycerol monostearate, cetostearyl alcohol, cetomacrogolemulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g.,macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oilderivatives, polyoxyethylene sorbitan fatty acid esters (e.g., thecommercially available Tweens® such as e.g., Tween 20® and Tween 80®(ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowax 3350®and 1450®, and Carbopol 934® (Union Carbide)), dodecyl trimethylammonium bromide, polyoxyethylene stearates, collodial silicon dioxide,phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol, superione, and triton),poloxamers (e.g., Pluronics F68® and F108®, which are block copolymersof ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic908®, also known as Poloxamine 908®, which is a tetrafunctional blockcopolymer derived from sequential addition of propylene oxide andethylene oxide to ethylenediamine (BASF Wyandotte Corporation,Parsippany, N.J.)); a charged phospholipid such as dimyristoylphophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic 1508®(T-1508) (BASF Wyandotte Corporation), dialkylesters of sodiumsulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester ofsodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is asodium lauryl sulfate (DuPont); Tritons X-200, which is an alkyl arylpolyether sulfonate (Rohm and Haas); Crodestas F-1100, which is amixture of sucrose stearate and sucrose distearate (Croda Inc.);p-isononylphenoxypoly-(glycidol), also known as Olin-10G® or Surfactant10-G® (Olin Chemicals, Stamford, Conn.); Crodestas SL-40® (Croda, Inc.);and SA9OHCO, which is C₁₈H₃₇CH₂(CON(CH3))-CH₂(CHOH)₄(CH₂OH)₂ (EastmanKodak Co.); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside;n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecylβ-D-maltoside; heptanoyl-N-methylglucamide;n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexylβ-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonylβ-D-glucopyranoside; octanoyl-N-methylglucamide;n-octyl-β-D-glucopyranoside; octyl β-D-thioglucopyranoside; and thelike.

Most of these fluids containing stabilizer are known pharmaceuticalexcipients and are described in detail in the Handbook of PharmaceuticalExcipients, published jointly by the American Pharmaceutical Associationand The Pharmaceutical Society of Great Britain (The PharmaceuticalSociety of Great Britain (The Pharmaceutical Press, 1986), specificallyincorporated by reference.

The fluid containing stabilizers are present in the formulation ofpresent invention in an amount within the range from about 0.2 to about10% w/v of total formulation, preferably for about 0.5 to about 5% ofthe total formulation. Preferably, the amount of fluid containingstabilizer in present invention are from about 0.5 mg to about 30 mg ofthe total formulation, preferably, about 1 mg to about 20 mg of totalformulation.

The matrix forming agent of present composition is selected frompolyethylene glycol, sodium carboxymethyl cellulose, hydroxypropylcellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose,hydroxypropylmethyl cellulose, polyethylene glycols, polyoxyethylene andpolyoxypropylene ethers and polyvinylpyrrolidone, with sodiumcarboxymethyl cellulose and polyvinylpyrrolidone being preferred,although other suitable matrix forming agents may also be used. Thepreferred matrix forming agent is polyethylene glycol. Suitable liquidcrystalline matrix forming agent may be used in present invention suchas glyceryl monoleate, glycerylmonostearate and the combinationsthereof. The matrix forming agent are present in the formulation ofpresent invention in an amount within the range from about 0.2% to about10% w/v of total formulation.

The viscosity enhancing agent of present invention that increases theviscosity of the injection vehicle is selected from sorbitol, glycerin,propylene glycol and such other solvents may also be used. The viscosityenhancing agent are present in the formulation of present invention inan amount within the range from about 5% to about 15% w/v of totalformulation.

Suitable “in-situ” gel-forming agents of the present invention convertto gels while preparation of the formulation and thus also act asviscosity enhancing agent. Such agents are selected from sucrose acetateisobutyrate, poly N,N-dimethyl acrylamide, poly(methyl vinyl ether),poly (N-vinyl caprolactam), Pluronics, PLGA and PLA. The “in-situ”gel-forming agents are present in the formulation of present inventionin an amount within the range from about 40% to about 75% w/w of totalformulation.

Pharmaceutically acceptable preservatives are antimicrobials andanti-oxidants used in the present invention which can be selected fromthe group consisting of benzyl alcohol, benzyl benzoate, methyl paraben,propyl paraben benzoic acid, butylated hydroxyanisole, butylatedhydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol,chlorocresol, metacresol, benzethonium chloride, myristyl-γ-piccoliniumchloride, phenylmercuric acetate and thimerosal. In particular, methylparaben and propyl paraben can be used in the range of 0.01%-0.18% w/vof total formulation, benzyl alcohol can be used in the range of 0.5% to10% w/v of total formulation.

Suitable buffering agents used in present invention are salt of weakacids and should be used in amount sufficient to render the formulationneutral to very slightly basic (up to pH 8.5), preferably in the pHrange of 7 to 7.5. Particularly preferred is the use of a mixture ofdisodium hydrogen phosphate (anhydrous). The pH may also be adjusted bythe addition of suitable acids and bases such as sodium hydroxide,hydrochloric acid, glacial acetic acid and the combination thereof.

Pharmaceutically acceptable isotonizing agents used in present inventionare, for example, sodium chloride, dextrose, mannitol, sorbitol,lactose, sodium sulfate. The formulation of present invention comprisesfrom 1% to 10% (w/v) isotonizing agent. Preferably, mannitol is used ina concentration from 2% to 7% (w/v), more preferably about 5%. Mostpreferably, however, from about 1% to about 3% (w/v), especially fromabout 1.5% to about 2% (w/v) of one or more electrolytes are used torender the suspension isotonic. In addition, electrolytes have thefurther advantage of buffering the aqueous suspension. Particularlypreferred is the use of a mixture of disodium hydrogen phosphate(anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogen phosphatemonohydrate (typically about 0.6% (w/v)) for rendering the solutionisotonic, neutral and less prone to flocculation of the suspended estertherein. The tonicity adjusting agents adjust the tonicity to precludetoxicity problems and improve biocompatibility. The tonicity adjustingagent of present invention may be selected from, but not limited tosodium chloride, dextrose, potassium chloride, mannitol, and glycerin,although other suitable tonicity adjusting agents may also be used.

Suitable lipids used in the formulation of present invention are capableof forming complex with varenicline or its pharmaceutically acceptablesalt such as phosphatidylcholine (PC) or purified egg yolk lecithin,phosphatidylethanolamine (PE), phosphatidylserine (PS),phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol(PI), sphingomyelin (SPM), and the like, alone or in combination.Saturated phospholipids such as hydrogenated soy PC may also be used.The phospholipids can be synthetic or derived from natural sources suchas egg or soy. In the preferred embodiments, the phospholipids used inthe present formulation are dimyristoylphosphatidylcholine (DMPC) anddimyristoylphosphatidylglycerol (DMPG),1,2-distearoyl-sn-glycero-3-phosphocholine sodium (DSPG-Na),dipalmitoylphosphatidylcholine (DPPC), hydrogenated soya phosphatidylcholine (HSPC), phosphatidyl-N-methylethanolamine (PE-Me), orcombinations thereof.

Suitable vehicle used in present invention are water for injection,glycerin and the combinations thereof. Other vehicle used in presentinvention when the desired dosage form is an oily solution includevegetable oils selected from cottonseed oil, castor oil, sesame oil,arachis oil, oleic acid, ethyl undecanoate, almond oil, coconut oil,olive oil, soybean oil, (purified) tri-glycerides, propylene glycolesters, ethyl oleate, linseed oil, sunflower oil, peanut oil, olive oil,wheat-germ oil and similar oils and the combinations thereof.

The pharmacokinetic properties of the formulations according to thepresent invention further may depend to a limited extent on thephysicochemical properties of the drug, such as the particle size andcrystal form.

A particularly desirable feature for an injectable depot compositionrelates to the ease with which it can be administered. In particular,such an injection should be feasible using a needle as fine as possiblein a span of time which is as short as possible. This can beaccomplished with the aqueous suspensions of the present invention bykeeping the viscosity below about 75 mPa·s, preferably below 60 mPa·s.Aqueous suspensions of such viscosity or lower can both easily be takenup in a syringe (e.g. from a vial), and injected through a fine needle(e.g., a 21 G 1½, 26 G 1, 22 G 2 or 22 G 1¼ needle).

The present invention also provides a process for preparing the longacting depot formulation, which process comprises admixing apharmaceutically acceptable solvent/s or excipient/s with varenicline orits salts.

In some embodiments, methods used for preparation of the presentinvention may be selected from high sheer homogenization, high pressurehomogenization, Ultrasonication/high speed homogenization, admixture ofsolvents, solubilizers and actives to prepare suspension, solventemulsification/evaporation etc. A preferred method is high sheerhomogenization. In another embodiment, the method used for particle sizereduction of varenicline of present invention may be selected fromsonication, cryomilling or other processes inducing high shear in thepresence of phospholipid or other membrane-forming amphipathic lipid. Apreferred method is cryomilling for particle size reduction ofvarenicline.

In some embodiments, the long-acting depot composition of varenicline issupplied in an injection volume of 0.5 ml to 2.5 ml in a prefilled vial.

A person skilled in the art for preparing formulations according to thepresent invention will understand that the proportions of componentswith respect to each other will vary depending on the specificcomponents used. For example, the use of different solubilizers andstabilizers will require some straightforward modifications to theproportions, depending on the compatibility and miscibility of aparticular stabilizer in a particular vehicle.

In embodiments, the excipients for the present invention may be selectedfrom, but not limited to, the range of pharmaceutically acceptableexcipients, which are soluble in the aqueous solvent system and whichare also compatible with the active ingredient. The excipients selectedfor the purpose of the present invention do not create any degenerativeeffect on the active ingredient such as varenicline.

The present invention also provides a method of using the formulation ofpresent invention as an aid in smoking cessation treatment, comprisingadministering pharmaceutical long acting depot formulation comprising atherapeutically effective amount of varenicline or its pharmaceuticallyacceptable salt of varenicline.

The present invention also provides a long acting depot formulation foruse as an aid in smoking cessation treatment by administeringpharmaceutical long acting depot composition comprising atherapeutically effective amount of a pharmaceutically acceptable saltof varenicline.

The present invention also provides a method for reducing nicotineaddiction, aiding in the cessation of, or lessening of, tobacco use in asubject by administering a long acting depot formulation comprisingvarenicline or its pharmaceutically acceptable salt and one or morepharmaceutically acceptable excipients.

The following examples are for the purpose of illustration of theinvention only and are not intended in any way to limit the scope of thepresent invention. In the examples, varenicline as the free base wasemployed to prepare the depot formulations.

Example 1: Oily Solution

TABLE 1 Composition of oily solution Ingredients Quantity (% w/v)Varenicline    2%-40% Benzyl benzoate   10%-50% Benzyl alcohol  0.5%-10% Cottonseed oil/Castor oil/Sesame oil qs 0.5%-1.5%

Procedure:

-   -   1. Benzyl benzoate, benzyl alcohol and castor oil/cottonseed        oil/sesame oil were mixed.    -   2. Varenicline was added to the mixture with stirring and heated        if required.

Example 2: Varenicline-Lipid Complex Formulation for IntramuscularInjection

TABLE 2 Composition of varenicline- lipid complex formulationIngredients Quantity (% w/v) Varenicline 2%-40% w/v Purified egg yolklecithin 10%-80% w/v Polysorbate 80 0.5%-5% Water q.s. 0.5 ml-1.5 ml 

Procedure:

1. Purified egg yolk lecithin and varenicline were dissolved indichloromethane and a thin drug lipid film was prepared using rotaryevaporation.

2. Polysorbate 80 was dissolved in water to prepare aqueous phase.

3. The above aqueous phase containing the Polysorbate 80 was added tothe varenicline-lipid film and homogenized.

Example 3: Intramuscular (IM) Depot Injection—Microspheres

TABLE 3 Composition of varenicline microspheres Ingredients Quantity (%w/w) Varenicline  2%-40% *Biodegradable polymer 60%-95% *Biodegradablepolymers: PLA, PLGA 75:25, PLGA 50:50, PCL.

Procedure:

-   -   1. Varenicline and polymer were dissolved in dichloromethane        (organic phase)    -   2. Polyvinyl alcohol and mannitol were dissolved in the required        quantity of water for the external phase.    -   3. The organic phase of step 1 was added to the external phase        of step 2 under continuous homogenization.    -   4. The above solution/suspension was stirred for 2-3 hrs, and        filtered under vacuum.    -   5. The microsphere powder was washed and dried.    -   6.

Example 4: Implants

TABLE 4 Composition of varenicline implants Ingredients Quantity (% w/w)Varenicline  2%-40% *Biodegradable/Non biodegradable polymer 60%-95%Biodegradable polymers: PLA, PLGA 75:25, PLGA 50:50, PCL. Nonbiodegradable polymer: EVA, Polyurethane

Procedure:

-   -   1. Varenicline and polymer were cryomilled.    -   2. The polymer-varenicline powder mixture was introduced into        hot melt extruder.    -   3. The extrudes were then cut to desired length.

Example 5: Liquid Crystalline Systems (Cubosomes/Hexosomes)

TABLE 5 Composition of varenicline cubosomes/hexosomes IngredientsQuantity (% w/v) Varenicline  2%-40% Glyceryl mono-oleate/Glycerylmonostearate 80%-90% Polysorbate 80 0-5%

Procedure:

-   -   1. Glyceryl mono-oleate/Glyceryl monostearate and polysorbate 80        were dissolved in water under stirring.    -   2. Varenicline was added to the above mixture.    -   3. After complete addition of varenicline, the mixture was        vortexed.

Example 6: In Situ Gelling System

TABLE 6 Composition of in-situ gelling system Ingredients Quantity (%w/v) Varenicline  2%-40% Sucrose acetate isobutyrate (SAIB) 40%-75%Ethanol 2%-5% Glycerin  5%-15%

Procedure:

-   -   1. Sucrose acetate isobutyrate, ethanol and glycerin were mixed        under stirring.    -   2. Varenicline was added to the above mixture and stirred till a        homogenous mixture is formed.    -   3. The mixture was heated only if required.

Example 7: In Situ Gelling System

TABLE 7 Composition of in-situ gelling system Ingredients Quantity (%w/v) Varenicline  2%-40% N-methyl-2-pyrollidone 10%-25% *Biodegradablepolymer 2%-5% Biodegradable polymers: PLA, PLGA 75:25, PLGA 50:50, PCL.

Procedure:

-   -   1. Varenicline and polymer were mixed in N-methyl-2-pyrollidone        under stirring.    -   2. The above mixture was stirred till a homogenous mixture was        formed.    -   3. The mixture was heated only if required.

Example 8: Aqueous Suspension

TABLE 8 Composition of aqueous suspension Ingredients Quantity (% w/v)Varenicline   2%-40% Sodium carboxy methylcellulose  1%-3% Polysorbate80 0.5%-5% Benzyl alcohol 0.5%-1% Water qs 0.5 ml-1.5 ml 

Procedure:

-   -   1. Sodium carboxy methylcellulose, polysorbate 80 and benzyl        alcohol were dissolved in required quantity of water under        stirring.    -   2. Varenicline was added to solution of step 1 and stirred till        a homogenous suspension is formed.    -   3. The volume was made up with water, if required.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the spirit of the invention. Thus, itshould be understood that although the present invention has beenspecifically disclosed by the preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and such modificationsand variations are considered to fall within the scope of the invention.

It is to be understood that the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having” andvariations thereof herein is meant to encompass the items listedthereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referencesunless the context clearly dictates otherwise. Thus, for example,reference to “an excipient” includes a single excipient as well as twoor more different excipients, and the like.

We claim:
 1. A pharmaceutical long-acting depot composition comprisingvarenicline, or a pharmaceutically acceptable derivative thereof, andone or more pharmaceutically acceptable excipients dispersed inbiodegradable carrier, wherein after administration to a subject in needthereof, the composition delivers a therapeutic dose of varenicline fora period of at least one week.
 2. The composition according to claim 1,wherein the particle size (d₉₀) of varenicline in the composition isfrom about 20 microns to about 100 microns.
 3. The composition accordingto claim 1, wherein the particle size (d₉₀) of varenicline in thecomposition is from about 40 microns to about 80 microns.
 4. Thecomposition according to claim 1, wherein the therapeutic dose is fromabout 0.05 mg to about 5 mg per day.
 5. The composition according toclaim 1, wherein the biodegradable carrier is in the form ofmicrospheres, implants, cubosomes, hexosomes, solutions, suspensions,microemulsions, in-situ gelling system, or a combination thereof.
 6. Thecomposition according to claim 5, wherein the biodegradable carriercomprises polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA) 75:25,PLGA 50:50, polycaprolactone (PCL), linear polyhydroxy alkanoate (PHA),polybutylene succinate (PBS), polybutylene succinate adipate (PBSA),polybutylene adipate (PBA), polybutylene adipate terephthalate (PBAT),polycarbonates, polyurethanes, ethylene-vinyl acetate (EVA),polyurethane, or combination thereof.
 7. The composition according toclaim 1, wherein the one or more pharmaceutically acceptable excipientsare selected from stabilizers, matrix forming agents, lipids, viscosityenhancing agents, preservatives, buffering agents, isotonizing agents,injection vehicles, and combinations thereof.
 8. The compositionaccording to claim 7, wherein the stabilizer is selected frompolyoxyethylene derivatives of sorbitan esters, lecithin,polyoxyethylene ethers, polyoxypropylene ethers, sodium deoxycholate,and combinations thereof.
 9. The composition according to claim 7,wherein the matrix forming agent is selected from polyethylene glycol,sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose,polyethylene glycols, polyoxyethylene, polyoxy-propylene ethers,polyvinylpyrrolidone, and combinations thereof.
 10. The compositionaccording to claim 7, wherein the lipid is selected fromphosphatidylcholine, purified egg yolk lecithin,phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol,phosphatidic acid, phosphatidylinositol, sphingomyelin, hydrogenated soyphosphatidylcholine, dimyristoylphosphatidylcholine,dimyristoylphosphatidylglycerol,1,2-distearoyl-sn-glycero-3-phosphocholine sodium,dipalmitoylphosphatidylcholine, hydrogenated soya phosphatidyl choline,phosphatidyl-N-methylethanolamine, and combinations thereof.
 11. Thecomposition according to claim 7, wherein the viscosity enhancing agentis selected from sorbitol, glycerin, propylene glycol, and combinationthereof.
 12. The composition according to claim 7, wherein thepreservative is selected from benzyl alcohol, benzyl benzoate, methylparaben, propyl paraben benzoic acid, butylated hydroxyanisole,butylated hydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate,EDTA, phenol, chlorocresol, metacresol, benzethonium chloride,myristyl-β-piccolinium chloride, phenylmercuric acetate, thimerosal, andcombinations thereof.
 13. The composition according to claim 7, whereinthe injection vehicle is selected from water for injection, glycerinvegetable oil, oleic acid, ethyl undecanoate, almond oil, coconut oil,olive oil, soybean oil, (purified) triglycerides, propylene glycolesters, ethyl oleate, linseed oil, sunflower oil, peanut oil, olive oil,wheat-germ oil and combinations thereof.
 14. The composition accordingto claim 1, wherein the composition is an aqueous suspension comprisingvarenicline, or a pharmaceutically acceptable derivative thereof, andone or more pharmaceutically acceptable excipients selected from CMC,polysorbate 80, benzyl alcohol, or a combination thereof.
 15. Thecomposition according to claim 1, wherein the viscosity of thecomposition is below about 75 mPa*s.
 16. The composition according toclaim 1, wherein the varenicline, or a pharmaceutically acceptablederivative thereof, is present in an amount from about 1% to about 50%w/v of the total composition.
 17. The composition according to claim 1,wherein the varenicline is present as the free base.
 18. The compositionaccording to claim 1, having a pH from 7 to 7.5.
 19. The compositionaccording to claim 1, wherein the composition is a water-in-oil waterdouble emulsion.
 20. The composition according to claim 1, wherein thecomposition is an aqueous suspension.